Mice given ‘exercise in a pill’ show ‘huge increase’ in endurance, say Salk scientists

Mice given a compound that activates the gene PPARD were able to run long distances in a Salk study.

When scientists at the Salk Institute gave mice a chemical compound that mimics the beneficial effects of exercise, something extraordinary happened: The critters ran on a treadmill for 270 minutes—70% longer than mice that were not given the pill. The researchers hope those results can be translated into a medication to help not just people who are trying to lose weight, but also those who are unable to exercise because of age or mobility limitations.

The extra minutes that the mice ran marked “a huge increase in performance for sedentary mice that never actually trained,” said Salk’s Ronald Evans, the senior author of the study, in a video released by the organization (see below). “And it would take a lot of diligent training, every single day, to get that benefit. And these mice are getting it just because we’re feeding them a drug that’s reprogramming their metabolic properties.” The research was published in the journal Cell Metabolism.

The drug the Salk team developed was based on prior work at the institute to pinpoint a gene pathway that’s triggered by running, according to a press release. They key is a gene called PPAR delta (PPARD). They discovered that when mice were genetically engineered so their PPARD genes were permanently turned on, they could run for long distances without getting exhausted, they were resistant to weight gain and they were responsive to insulin. In other words, they had all the properties of people who are physically fit.

The Salk scientists landed on a chemical compound called GW1516 that seemed to activate PPARD, but it didn’t enhance endurance in the mice on its own—they still had to train to be able to run long distances.

So in this study, the researchers upped the dose of GW1516 and gave it to the mice for 8 weeks instead of just 4. That did the trick.

Evans’ team wanted to know what was happening at a genetic level in the muscles of the mice, so they scrutinized 975 genes that seemed to change in response to GW1516. They found that the genes that became overly active were the ones involved in burning fat, while the genes that were suppressed were instrumental in turning carbohydrates into energy. They concluded that PPARD is suppressing sugar metabolism in muscle, so glucose can be redirected to the brain. That may explain why some runners eventually hit a wall—becoming mentally and physically fatigued after long distances.

The research marks the latest in a string of studies out of Salk designed to improve the management of obesity, diabetes and other metabolic disorders. In 2015, Evans nabbed $36 million to launch a startup, Metacrine, which is developing drugs based on some of the research out of his lab. The company started up with two compounds: an insulin sensitizer to treat diabetes, and a potential treatment for liver disease.

As for the exercise-in-a-pill idea, Evans’ team envisions several potential applications, including a prescription drug to help people with obesity or type 2 diabetes burn fat, and to make it easier for patients to become fit before or after surgery. Salk has not provided any details on next steps, saying only in the release that “pharmaceutical companies are interested in using the research to develop clinical trials for humans.”